MPI Pyrophosphate Kit Kit for the Preparation of Technetium Tc 99m Pyrophosphate DIAGNOSTIC-FOR INTRAVENOUS USE

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1 MPI Pyrophosphate Kit Kit for the Preparation of Technetium Tc 99m Pyrophosphate DIAGNOSTIC-FOR INTRAVENOUS USE DESCRIPTION: Each reaction vial contains 40 mg sodium pyrophosphate (equivalent to 23.9 mg anhydrous sodium pyrophosphate) and 0.4 mg stannous fluoride (minimum) and 0.9 mg total tin (maximum) as stannous fluoride; the product does not contain a preservative. The ph of the product is adjusted with sodium hydroxide or hydrochloric acid prior to lyophilization. At the time of manufacture, the air in the vial is replaced with a nitrogen gas atmosphere. The ph of the reconstituted product is 5.5 to 6.9. When sterile, non-pyrogenic sodium pertechnetate Tc 99m solution is added to the vial, a diagnostic agent, technetium Tc 99m Pyrophosphate, is formed for intravenous administration; the structure of this radiolabeled complex is unknown. The product as supplied is sterile and nonpyrogenic. PHYSICAL CHARACTERISTICS: Technetium Tc 99m decays by isometric transition with a physical half-life of 6.02 hours. The principal photon that is useful for detection and imaging studies is shown intable 1. Table 1. Principal Radiation Emission Data 1 Radiation Mean %/Disintegration Mean Energy (kev) Gamma 'Kocher, David C., "Radioactive Decay Data Tables," DOE/ TIC (1981). EXTERNAL RADIATION: The specific gamma ray constant for Tc 99m is 0.78 R/hour-millicurie at 1 cm. The first half-value layer is cm of lead (Pb). A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb is shown in Table 2. To facilitate control of the radiation exposure from millicurie amounts of this radionuclide, the use of a 0.25 cm thickness of Pb will attenuate the radiation emitted by a factor of 1,000. Table 2. Radiation Attenuation of Lead (Pb) Shielding Shield Thickness (Pb)cm Coefficient of Attennuation To correct for physical decay of this radionuclide the fractions that remain at selected intervals after the time of calibration are shown in Table 3. TABLE 3 Physical Decay Chart: Tc 99m half-life 6 02 hours Hours 0 * Fraction Remaining Calibration Time Hours Fraction Remaining CLINICAL PHARMACOLOGY: Bone and Cardiac Imaging: Following intravenous administration of the technetium Tc99m pyrophosphate, skeletal uptake occurs as a function of blood flow to bone and bone efficiency in extracting the complex. Bone mineral crystals are generally considered to be hydroxyapatite, and the complex appears to have an affinity for the hydroxyapatite crystals in bone. It is theorized that the

2 complex also reacts with the mitochondrial calcium crystals, produced within infarcted myocardial cells which are believed to be hydroxyapatite; this phenomenon usually does not persist beyond six days after the occurrence of an infarction. Clearance of the radioactivity from the blood is quite rapid with skeletal uptake and urinary excretion being the principal mechanisms of clearance. At two hours following intravenous injection, approximately 55 percent of the injected dose has localized in bone; at four hours approximately 10 percent of the dose remains in the vascular system, decreasing to about 7 percent at 24 hours. The average urinary excretion was observed to be about 38 percent of the administered dose after eight hours increasing to an average of about 44 percent at 24 hours. A minimum amount of uptake has been observed in soft-tissue organs, most notably the kidneys. Blood Pool Imaging: The in vivo tagging of MPI Pyrophosphate Kit results in the radiolabelling of red blood cells. Approximately 76 percent of the injected activity remains in the blood pool between 30 and 60 minutes after injection of sodium pertechnetate Tc 99m, thereby permitting excellent images of the cardiac chambers. Maximum blood radioactivity levels occur in about 30 minutes; the initial biological half-life is approximately 18 hours. There is virtually no biological elimination of the agent after approximately six hours. INDICATIONS AND USAGE: Bone Imaging: MP! Pyrophosphate Kit (Kit for the Preparation of Technetium Tc 99m Pyrophosphate) may be used as a bone imaging agent to delineate areas of altered osteogenesis. Cardiac Imaging: MPI Pyrophosphate Kit is a cardiac imaging agent used as an adjunct in the diagnosis of acute myocardial infarction. The infarction is best visualized one to six days after onset of symptoms. False-negative images can occur if imaging is done too early in the evolutionary phase of the infarct or too late in the resolution phase. The incidence of false-positives may range from 5 to 9 percent and of false-negatives from 6 to 9 percent but may vary even more depending on selection criteria of patient populations. Blood Pool Imaging: MPI Pyrophosphate Kit is also a blood pool imaging agent which may be used for gated cardiac blood pool imaging and for the detection of sites of gastrointestinal bleeding. When administered intravenously 15 to 60 minutes prior to intravenous administration of sodium pertechneetatetc99m, approximately 75% of the injected activity remains in the blood pool. CONTRAINDICATIONS: None known. WARNINGS: Preliminary reports indicate impairment of brain scans using sodium pertechnetate Tc 99m injection which have been preceded by a bone scan using an agent containing stannous ions. The impairment may result in false-positive or false-negative brain scans. It is recommended, where feasible, that brain scans precede bone imaging procedures. Alternatively, a brain-imaging agent such as technetium Tc 99m pentetate may be employed. PRECAUTIONS: General: The lyophilized contents of the MPI Pyrophosphate Kit reaction vial are to be administered to the patient only as an intravenous solution (see PROCEDURES FOR RECONSTITUTION OF MPI PYROPHOSPHATE KIT). Any sodium pertechnetate Tc 99m solution which contains an oxidizing agent is not suitable for use with MPI Pyrophosphate Kit (Kit for the Preparation of Technetium Tc 99m Pyrophosphate). When reconstituted with sodium pertechnetate Tc 99m, MPI Pyrophosphate Kit must be used within 6 hours. When reconstituted with Sodium Chloride Injection USP for blood pool imaging, use the solution within 30 minutes. The imaging of gastrointestinal bleeding is dependent on such factors as the region of imaging, rate and volume of the bleed, efficacy of labeling of the red blood cells and timeliness of imaging. Due to these factors, images should be taken sequentially over a period of time until a positive image is obtained or clinical conditions warrant the discontinuance of the procedure. The period of time for collecting the images may range up to thirty-six hours. Technetium Tc 99m pyrophosphate as well as other radioactive drugs must be handled with care, and appropriate safety measures should be used to minimize radiation exposure to the patient and occupational workers consistent with proper patient management. Radiopharmaceuticals should be used only by physicians who are qualified by training and experience In the safe use and handling of radionuclides and whose experience and training have bean approved by the appropriate government agency authorized to license the use of radionuclides. Bone Imaging: Both prior to and following administration of the technetium Tc 99m pyrophosphate, the patient should be encouraged to drink fluids and to void as often as possible thereafter to minimize radiation exposure to the bladder and background interference during Imaging. Cardiac Imaging: The patient's cardiac condition should be stable before beginning the cardiac imaging procedure. If not contraindicated by the patient s cardiac status, patients should be encouraged to drink fluids and to void as often as possible in order to reduce unnecessary radiation exposure to the bladder. Interference from chest wall lesions such as breast tumors and healing rib fractures can be minimized by employing the three recommended projections (see DOSAGE AND ADMINISTRATION). False-positive and false-negative myocardial scans may occur, therefore, the diagnosis of acute myocardial infarction depends on the overall assessment of laboratory and clinical findings.

3 Blood Pool Imaging: The reconstituted agent should be Injected by direct venipuncture. Heparinized catheter systems should be avoided, as interference with red blood cell tagging will result. Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term animal studies have been performed to determine any carcinogenic potential or impairment of fertility in males or females. Teratogenic Effects: Pregnancy Category C: Animal reproduction studies have not been conducted with technetium Tc 99m pyrophosphate. It is also not known whether technetium Tc 99m pyrophosphate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Technetium Tc 99m pyrophosphate should be administered to a pregnant woman only If clearly needed. Ideally, examinations using radiopharmaceuticals, especially those elective in nature, in women of childbearing capability should be performed during the first few (approximately 10) days following the onset of menses. Nursing Mothers: Caution should be exercised when technetium Tc 99m pyrophosphate is administered to a nursing woman. Technetium Tc 99m is excreted in human milk during lactation; therefore, formula-feedings should be substituted for breastfeedings. Pediatric Use: Safety and effectiveness in children have not been established. ADVERSE REACTIONS: Several adverse reactions due to technetium Tc 99m pyrophosphate have been reported. These were usually hypersensitivity reactions characterized by itching, various skin rashes, hypotension, fever, chills, nausea, vomiting and dizziness. DOSAGEAND ADMINISTRATION: The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Intravenous doses for an average adult (70 kg) are as follows: Bone Imaging: The suggested dose is 370 to 555MBq (10 to 15 mci). Following reconstitution, technetium Tc 99m pyrophosphate is injected intravenously over a 10-to 20-second period. Imaging may be started at one hour after administration; however, for optimal results bone imaging should be performed two to four hours following administration. Cardiac Imaging: The suggested dose is 370 to 555 MBq (10 to 15 mci) administered intravenously over 10 to 20 seconds and within 24 hours to six days after the onset of symptoms suggestive of acute myocardial infarctlon. Imaging is recommended at 45 to 60 minutes post inject ion. It is suggested that scans be obtained in at least three projections (e.g., anterior, lateral, and left anterior oblique). Blood Pool Imaging: The suggested dose is 41 mg (contents of one reaction vial) of MPI Pyrophosphate Kit (see PROCEDURE FOR RECONSTITUTION) administered intravenously, followed 15 to 60 minutes later by the intravenous administration of 740 MBq (20 mci) of sodium pertechnetate Tc99m. Administration should be made by direct venipuncture and not by heparinized catheter systems. Cardiac pool Imaging should be initialed 15 to 30 minutes after the administration of sodium pertechnetatetc 99m. RADIATION DOSIMETRY: The effective half-life was assumed to be equal to the physical half-life for all calculated values. The estimated absorbed radiation doses to an average adult (70 kg) from an intravenous injection are shown in Tables 4 and 5. Table 4. Estimated Absorbed Radiation Dose Bone and Cardiac Imaging Technetium Tc 99m Sodium Pyrophosphate Target Organ mgy/555 MBq rads/15 mci Total Body Kidenys Bone Marrow Skeleton * Bladder Wall 2-hr. void hr. void Ovaries 2-hr. void hr. void Testes 2-hr. void hr. void If patient voids frequently after radiopharmacueitcal is administered, this dose will be reduced slightly. * Dose at point of highest uptake may be a factor of 10 higher.

4 Table 5. Estimated Absorbed Radiation Dose Blood Pool Imaging * Sodium Pertechnetate Tc 99m 30 min. Post Injection with Pyrophosphate Target Organ mgy/740 MBq rads/20 mci Total Body Spleen Bladder Wall Testes Ovaries Blood * Assume 75% of the Sodium PertechnetateTc 99m labels red blood cells and the other 25% remains as pertechnetate. + if 25% excreted with 1 hour T b. Method of Calculation: MIRD Dose Estimate Report No. 8 J Nucl Med 17:74-77, HOW SUPPLIED: MPI Pyrophosphate Kit (Kit for the Preparation of Technetium Tc 99m Pyrophosphate) is supplied in a kit containing 10 reaction vials (5 ml size), 10 pressure-sensitive labels, and 1 package insert. STORAGE: Store the MPI Pyrophosphate Kit (Kit for the Preparation of Technetium Tc 99m Pyrophosphate) at 2º to 8 C. The reconstituted preparation should be refrigerated since the product does not contain a preservative. When reconstituted with sodium pertechnetate Tc 99m, MPI Pyrophosphate Kit must be used within 6 hours. When reconstituted with Sodium Chloride Injection USP for blood pool imaging, use the solution within 30 minutes. PROCEDURES FOR RECONSTITUTI0N OF MPI PYROPHOSPHATE KIT: Procedural Precautions:: The contents of the MPI Pyrophosphate Kit reaction vial are sterile and nonpyrogenic. Aseptic procedures should be used during reconstitution of MPI Pyrophosphate Kit and the withdrawal of doses for intravenous administration. The introduction of air in to the vial during the reconstitution step should be avoided. The MPI Technetium Tc 99m Generator may be used as the source of sodium pertechnetate Tc99m solution; other sources which have been shown by the user to be compatible with the ingredients of MPI Pyrophosphate Kit (Kit for the Preparation of Technetium Tc99m Pyrophosphate) may also be used. Reconstitutlon: Bone and Cardiaic Imaging: Technetium Tc 99m Pyrophosphate must be used within 6 hours. 1. Waterproof gloves should be worn during the preparation procedure. 2. Allow the contents of the reaction vial to come to room temperature. 3. Place reaction vial in an appropriate lead shield with a fitted cover. * 4. Swab the rubber closure of the reaction vial with a germicide. 5. Using a shielded syringe, slowly inject 2 to 4 ml [up to 2775 MBq (75 mci)] of sterile sodium pertechnetate Tc 99m solution into the reaction vial. In determining the amount of technetium Tc 99m radioactivity to be used, the labeling efficiency, number of patients, administered radioactive dose and radioactive decay must be taken into account. NOTE: If sodium pertechnetate Tc 99m solution must be diluted for use with MPI Pyrophosphate Kit (Kit for the Preparation of Technetium Tc 99m Pyrophosphate), only Sodium Chloride Injection USP (without preservatives) should be used. 6. Secure the lead shield cover. Shake the vial gently to bring the lyophilized material into solution. 7. Record the time and date ol preparation and the radioconcentration and volume of the solution on the pressure-sensitive label. 8. Affix the pressure-sensitive label to the shield. 9. Using proper shielding, examine vial contents. If the solution is not clear and free of particulate matter and discoloration on visual inspection, it should not be used. 10. Maintain adequate shielding of the radioactive preparation including the use of appropriate shielded syringes. 11. Radioassay of technetium Tc 99m pyrophosphate may be accomplished conveniently by using an ionization chamber-type dose calibrator. Blood Pool Imaging: When reconstituted with Sodium Chloride Injection USP, MPI Pyrophosphate Kit should be used within 30 minutes. 1. Allow the contents of the reaction vial to come to room temperature. Swab the top of the rubber closure with a germicide. 2. Slowly inject 2 to 5 ml Sodium Chloride Injection USP (without preservatives) into the reaction vial. 3. Shake the vial gently to bring the lyophilized material into solution 4. If the solution is not clear and free of particulate matter and discoloration on visual inspection it should not be used. The US. Nuclear Regulatory Commission has approved this reagent kit for distribution to persons licensed to use byproduct material identified in of 10 CFH Part 35, to persons who hold an equivalent license issued by an Agreement State, and, outside the United States, to persons authorized by the appropriate authority.

5 Manufactured By: Squibb Diagnostics Princeton, NJ For Medi-Physics, Inc N. Ridge Avenue, Arlington Heights, Illinois Printed In USA Revised November 1990

TECHNESCAN PYP- technetium tc 99m pyrophos phate injection, powder, lyophilized, for solution Mallinckrodt Inc TechneScan PYP

TECHNESCAN PYP- technetium tc 99m pyrophos phate injection, powder, lyophilized, for solution Mallinckrodt Inc. ---------- TechneScan PYP Kit for the Preparation of Technetium Tc 99m Pyrophos phate Injection